Cyclin E cytoplasmatic isoform to predict outcome and benefit to capecitabine treatment in patients with HR+/HER2- metastatic breast cancer from the GEICAM/2013-02 PEARL study.
Authors: Angel Guerrero, Miguel J. Gil Gil, Christoph Zielinski, Manuel Ruiz-Borrego, Eva M Ciruelos, Montserrat Muñoz, Laura Murillo, Serafin Morales Murillo, Emilio Alba, Istvan Lang, Lourdes Calvo Martínez, Manuel Ramos Vazquez, Juan De La Haba, Jesus Herranz, Einav Nili Gal-Yam, Isabel Alvarez, Andres Garcia-Palomo, Ana Santaballa, Federico Rojo, Miguel Martin
Journal: Journal of Clinical Oncology (2023)

1023 Background: Cytoplasmic cyclin E protein expression, serving as a surrogate for the low molecular weight cyclin E isoform (LMW-E), is a biomarker associated with aggressive breast cancer and predicts resistance to aromatase inhibitors in luminal breast cancer. We investigated the prognostic and predictive value of cytoplasmic and nuclear isoforms of cyclin E in HR+/HER2- metastatic breast cancer (MBC) patients receiving palbociclib CDK4/6 inhibitor and endocrine therapy (PALBO+ET) versus capecitabine (CAPE) in the GEICAM/2013-02 PEARL trial (NCT02028507). Methods: Expression of Cytoplasmic and Nuclear isoforms of cyclin E were assessed by immunohistochemistry (IHC). An H-score based on the proportion and intensity of stained cells was explored using median value to categorize in Low / High expression the Nuclear and Cytoplasmic scores (N and C, respectively). In addition, N and C were independently assigned according to staining intensity (1 = no staining, 2 = weak, 3 = intermediate and 4 = strong staining) and then, combined in 4 phenotypes (Ph): Ph1 (N-/C-); Ph2 (N+/C-); Ph3 (N+/C+); and Ph4 (N-/C+), where negative=1-2, and positive=3-4. Cox regression models’ analysis were assessed to predict outcome and benefit to treatment, in terms of PFS and OS. Multivariate models were adjusted for confounders: age, site of disease, sites of metastasis, prior chemotherapy for MBC and treatment. Interaction analysis with treatment arm were performed. Results: Cyclin E protein was obtained from 344 tumors, with 73% being primary tumors and 27% metastatic. High expression of the Nuclear isoform was independently associated with significantly worse OS (median OS [mOS]=34.23 months [m] for low expression vs 25.72m for high expression; adjusted HR=1.48; p-value=0.016). Phenotype analysis supported this finding, with Ph3 (N+/C+) and Ph4 (N-/C+) demonstrating the worst (mOS=19.55m) and best (mOS=37.19m) outcomes, respectively (using Ph1 as reference, Ph3 HR=2.92; p-value=0.0013). The interaction between the treatment arm and Cytoplasmic cyclin E expression was significant (p=0.0052). Patients with high expression of the Cytoplasmic isoform had significantly better PFS with CAPE (mPFS=14.8m) than with PALBO + ET (mPFS=5.73m) (HR=1.9, p-value=0.0418). Ph4 (N-/C+) had also significantly better PFS for CAPE (mPFS=22.67m) than for PALBO + ET (mPFS=8.51m) (HR=2.94; p-value=0.036). Conclusions: This study confirms Cyclin E as a poor prognostic marker associated with worse overall survival in luminal MBC patients. Low molecular weight Cyclin E, detected as Cytoplasmic Cyclin E, identifies luminal MBC that benefit more from CAPE than from PALBO + ET. The low molecular weight Cyclin E isoform appears to be a promising predictive biomarker for the benefit of CAPE and resistance to PALBO + ET treatments in this population. Clinical trial information: NCT02028507 .